Product Standards for Reducing Nicotine in Cigarettes

Funding Research reported in this publication was supported by the National Institute on Drug Abuse and Food and Drug Administration Center for Tobacco Products (U54 DA031659). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration. Product Standards for Reducing Nicotine in Cigarettes Eric C. Donny, Ph.D. Professor, Department of Psychology, University of Pittsburgh Director, Center for the Evaluation of Nicotine in Cigarettes

Why do people smoke? People smoke for the nicotine -M.A. Russell, 1976

Why do people smoke? but they die from the tar -M.A. Russell, 1976

Why do people smoke? People smoke for the nicotine but they die from the tar -M.A. Russell, 1976

Why do people smoke? People smoke for the nicotine but they die from the tar -M.A. Russell, 1976 Nicotine Content

Family Smoking Prevention and Tobacco Control Act Enables FDA to set product standards for nicotine Cannot be reduced to zero Must consider the risks and benefits to the population as a whole including users and nonusers

Would a product standard requiring very low nicotine levels reduce cigarette use and improve public health?

Two sources of data for today Large clinical trial Rat self-administration

Donny et al., 2015 Purpose: To determine how use of cigarettes varying in nicotine content impacts a wide range of outcomes in a large study of smokers not currently interested in quitting

Design Double-blind, parallel, randomized trial 840 daily smokers 18+ years old 5+ CPD Not planning to quit in next 30 days

Design Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 AA Usual brand

Design Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 AA Study cigarettes provided free of charge All subjects menthol matched

Design Nicotine Nicotine Tar Content Yield (ISO) Yield (ISO) GROUPS (7 total) (mg/g) (mg/cig) (mg/cig) 1. Usual brand variable variable variable 2. Normal Nicotine 15.8 ~0.73 ~10 3. Reduced Nicotine 5.2 ~0.24 ~9 33% 4. Very Low Nicotine 2.4 ~0.11 ~9 15% 5. Very Low Nicotine 8% 1.3 ~0.06 ~8 6/7. Very Low Nicotine 3% 0.4 ~0.03 ~9 (or 13) Data provided by NIDA

Design Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 AA Abstinence Session

Design Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 AA 30 day Follow-up

Design Screen Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 AA In person visits (10) Outcome measures Smoking behavior Biomarkers Nicotine dependence Withdrawal and craving Safety

Design Compensation up to $835 Product use No incentive for compliance (or penalty for noncompliance) with study product Emphasis on honest reporting

Study sites

Sample characteristics Age: 42 Female: 42.3% African American: 39.7% High school or less: 44.2% Menthol preferred: 57% CPD: 15.5 CO: 15.1 FTND: 5.1

Does nicotine reduction lead to reduced smoking?

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Cigarettes per day Dose-dependent reduction in total CPD

Cigarettes per day Donny E.C. et al., 2015, NEJM, 373, 1340-9

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Cigarettes per day 5.2 and above 2.4 and below * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Hypothetical CPD at $6/pack * * * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Demand curve * 15.8 mg/g 0.4 mg/g 0 Cost

Take home point #1 Low nicotine content cigarettes reduce smoking relative to normal nicotine cigarettes CPD 0.4 vs. 15.8 mg/g Reduced Reduced Elasticity of demand (hypothetical)

Does nicotine reduction lead to compensatory smoking?

Compensatory smoking These Light cigarettes actually have reduced contain nicotine less nicotine. yield. It would The be content very difficult of the tobacco for smokers is the to same. adjust their With behavior light cigarettes, to maintain smokers nicotine can levels. and do compensate. Machine yield Content and user exposure

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Compensatory smoking No significant differences

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Compensatory smoking * * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Compensatory smoking Other studies also fail to find compensation that lasts beyond the first few cigarettes (Benowitz et al. 2012; Hatsukami et al., 2010, 2013, 2015; Donny et al., 2007; Donny and Jones, 2009; MacQueen et al., 2012) CPD similar or less than controls Carbon monoxide similar or less than controls Puff Volume similar or less than controls It is possible some subgroups will compensate (e.g., high dependence; Bandiera et al., 2015)

Take home point #2 Minimal evidence of compensatory smoking CPD CO Puff volume Filter analysis 0.4 vs. 15.8 mg/g Reduced Similar Reduced Underway

Does nicotine reduction lead to decreases in nicotine exposure?

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Biomarkers of exposure * * * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Content vs. Exposure Nicotine content Nicotine exposure 15.8 57% 0.4 97%

The Hotel Study 94% 24 participants smoked only 0.4 mg/g SPECTRUM while residing at a hotel for 4 nights. Nicotine exposure decreased by at least 92-94% 92%

Non-adherence Self-report: Each week, 30-60% of participants assigned to reduced nicotine cigarettes reported smoking other cigarettes. How much? 2-4 CPD (median when non-compliant) When? Most often first thing in morning Biomarkers: TNE at week 6 Only about 25% of participants in the 0.4 mg/g groups had TNE < 6.4 nmol/ml

Take home point #3 Low nicotine content cigarettes reduce nicotine exposure, but people seek out other sources of nicotine Clinical trial TNE Hotel TNE Clinical trial UB cigs 0.4 vs. 15.8 mg/g Reduced 57% Reduced >94% Increased

Does nicotine reduction reduce dependence and/or lead to quitting?

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Dependence * * * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Dependence * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Quit attempts * * *indicates significant (p<.0125) difference compared to 15.8 mg/g

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Cigarettes per day * * * *indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

Take home point #4 Low nicotine content cigarettes reduce nicotine dependence and may increase the likelihood that smokers will try to quit FTND & WIDSM Quit attempts at Follow-up CPD at Follow-up 0.4 vs. 15.8 mg/g Reduced Increased Reduced

Does nicotine reduction lead to other potentially harmful unintended consequences?

Potential unintended consequences Compensatory smoking Depression/disrupted affect Decreased positive Increased negative Weight gain Alcohol/drug use Impaired cognitive function Others AEs Platelet activation

Donny E.C. et al., 2015, NEJM, 373, 1340-9 Depression No significant differences in mean CESD scores Approximately 23% had a score 16+ at Week 6 No significant differences between groups 23% of 15.8 mg.g 22% of 0.4 mg/g CESD Maximum score: 60 Commonly use clinical cutoff: 16

Weight gain 0.4 mg/g conditions only * (n=56) (n=164) * * * *

Take home point #5 Low nicotine content cigarettes do not appear to increase depression, but do lead to expected gains in weight CESD Overall & >16 Weight 0.4 vs. 15.8 mg/g Similar Increased Note: a significant portion of participants use other products

Rat self-administration Sprague-Dawley rats 1-hr daily self-administration sessions Respond for intravenous (i.v.) infusions of nicotine

Smith et al., 2013 Nicotine and Tobacco Research

Smith et al., 2013 Nicotine and Tobacco Research Smith et al., 2013 Nicotine and Tobacco Research

Would nicotine reduction reduce the uptake of smoking?

Initiation of self-administration DOSE 15 60 7.5 3.75 0.0 The just ABOVE threshold dose from the reduction study The just BELOW threshold dose from the reduction study Adult male Sprague-Dawley rats Smith et al., 2014 Exp & Clinical Psychopharm

Initiation of self-administration Adolescents (male or female) fail to acquire at 10 ug/kg or lower Schassburger et al., under review, Nicotine and Tobacco Research

Take home point #6 Reducing nicotine may decrease the uptake of smoking # inf. % acq. Adolescents vs. adults low vs. high nicotine Reduced Reduced Similar or reduced sensitivity

Could other constituents maintain behavior?

Cigarette Smoke Constituents Nicotine: Primary reinforcing constituent > 8,000 other constituents

Cigarette Smoke Constituents Constituent Dose (µg/kg/inf) % Nicotine Minor alkaloids anabasine 0.9 3.0 anatabine 0.09 0.3 cotinine 0.09 0.3 myosmine 0.09 0.3 nornicotine 0.9 3.0 Beta-carbolines harman 0.1 0.3 norharman 0.3 1.0 Acetaldehyde 16 53 + Pre-session inj of MAO inhibitor, 1.0 mg/kg tranylcypromine (TCP)

Cigarette Smoke Constituents Smith et al., 2015, Drug and Alcohol Dependence Smith et al., Under Review

Cigarette Smoke Constituents FR3 FR5 Smith et al., 2015, Drug and Alcohol Dependence

Take home point #7 Although most other constituents may have little effect, constituents that inhibit MAO increase the reinforcing effects of low doses of nicotine # infusions at low cost # infusions at high cost Cocktail Non-sign Non-sign MAO inhibition Increased Non-sign

Take home points - summary 1) Very low nicotine content (VLNC) cigarettes reduces smoking relative to normal nicotine cigarettes. 2) VLNC cigarettes lead to minimal evidence for compensatory smoking. 3) VLNC cigarettes reduce nicotine exposure, but people seek out other sources of nicotine. 4) VLNC cigarettes reduce nicotine dependence and may increase the likelihood that smokers will try to quit. 5) VLNC cigarettes do not appear to increase depression in healthy volunteers, but do lead to weight gain similar to cessation. 6) Reducing nicotine decreases the uptake of self-administration in rats. 7) Non-nicotine constituents tend to have minimal effect on rat selfadministration, although constituents that inhibit MAO may increase the reinforcing effects of low doses of nicotine.

Conclusions Reducing nicotine in cigarettes and other combusted tobacco products could improve public health. Large reductions in nicotine content may be necessary to produce the optimal health impact.

Missing in action Core staff Many critically important RAs, students, physicians, nurses, and other staff at all the CENIC project sites NIDA, RTI and 22 nd century FDA & NIH Pitt general counsel and research compliance offices Anyone else I forgot!

Critical question for audience What additional data do you think are necessary before FDA should consider regulating the nicotine content of cigarettes?